title: HOXB13 downregulates intracellular zinc and increases NF-κB signaling to promote prostate cancer metastasis.
abstract: Characteristically, prostate cancer (PCa) cells exhibit marked decrease in intracellular zinc; however, the mechanism responsible is not clearly understood. HOXB13 is involved in PCa progression and is overexpressed in castration-resistant PCa. DNA microarray analysis of LNCaP Pca cells showed that ZnT zinc output transporters were strikingly upregulated among androgen-independent HOXB13 target genes. Furthermore, exogenous HOXB13 caused intracellular zinc concentrations to fall in PCa cells, stimulated NF-κB-mediated signaling by reducing inhibitor of NF-κB alpha (IκBα) and enhanced the nuclear translocation of RelA/p65. Human prostate tumors also exhibited strong inverse correlation between the protein expressions of HOXB13 and IκBα. Consequently, HOXB13 stimulated PCa cell invasion, and this was inhibited by the suppression of ZnT4. In addition, studies in a PC3 orthotopic mouse model of PCa metastasis showed that HOXB13 is a strong metastatic stimulator. Taken together, these results show that HOXB13 promotes PCa invasion and metastasis by decreasing intracellular zinc levels, thus stimulating NF-κB signals, and suggest that HOXB13 acts as a modulator of intracellular zinc levels that promotes the malignant characteristics of PCa.
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Y-R
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: I-J
authors.initials: IJ
authors.lastname: Kim
authors.affiliation: Department of Urology, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: T W
authors.initials: TW
authors.lastname: Kang
authors.affiliation: Department of Pathology, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: C
authors.initials: C
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: K K
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Statistics, College of Natural Sciences, Chonnam National University, Gwangju, Korea.
authors.forename: M S
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: K I
authors.initials: KI
authors.lastname: Nam
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: C
authors.initials: C
authors.lastname: Jung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D015032:Zinc / Q000737:chemistry*
chemical_list: C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; D020672:I-kappa B Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D015032:Zinc